The present invention relates to new bromothiazolium salts and chlorothiazolium salts and their use as condensation reagents, particularly as peptide coupling reagents, a process for their preparation, and intermediates needed in this process.
For the preparation of efficient peptide coupling reagents such as, for example, of the peptide coupling reagent 2-bromo-3-ethyl-4-methyl-thiazolium tetrafluoroborate (BEMT, see Tetrahedron Lett. 1999, 40, 8301–8304), published for the first time in 1999 by P. Li, bromothiazoles such as, for example, 2-bromo-4-methylthiazole are needed as immediate precursors. The processes known for the preparation of these compounds, particularly of 2-bromo-4-methylthiazole, are not satisfactory and are unsuitable for preparation on a molar or larger scale. The structurally similar, but less active reagent 2-bromo-1-ethyl-pyridinium tetrafluoro-borate (BEP, see Chem. Lett. 2000, 204–205) is, for example, significantly easier to prepare, longer known, and commercially obtainable. There is therefore a need for improved processes for the preparation of peptide coupling reagents such as BEMT and suitable bromothiazoles such as 2-bromo-4-methylthiazole and routes for their preparation.
There is likewise a need for further peptide coupling reagents that are employed with higher efficiency and can be prepared using practicable processes. Thus, for example, the 2-chlorothiazole derivative of BEMT, 2-chloro-3-ethyl-4-methylthiazole tetrafluoroborate (CEMT, CAS No. 667-86-7, Dalton Trans. (1974), 7, 760–764) and its precursor, 2-chloromethylthiazole (CMT, CAS No. 26847-01-8, JP 44/32,406) are known compounds. However, while BEMT has already been described as a coupling reagent, the chloro derivative (CEMT) has hitherto not been disclosed as a coupling reagent. The key structural unit for the preparation of CEMT, CMT has moreover always been prepared by means of a process route which, like the processes for the preparation of BEMT, has disadvantages (Raubenheimer, H. G. et al (1997), Organomet. Chem. 544, 91–100).
2-Bromo-4-methylthiazole can be prepared from 2-amino-4-methyl-thiazole by Sandmeyer reaction. The work-up is complicated and the yield of 32% of theory is unsatisfactory (cf. Yakugaku Zasshi 1960, 80, 1795 cited in C.A. 55:10417). Li, in 1999 (cf. above), only indicates a yield for the overall synthesis sequence for the preparation of BEMT that is not very satisfactory. In our own attempts to adjust this, it was additionally found that approximately 30% of 2,5-dibromo-4-methylthiazole is formed as an undesired and poorly separable by-product. A further synthesis route described is the bromination of 4-methylthiazole. The reaction with N-bromosuccinimide in tetrachloromethane has further disadvantages above and beyond the low yield of only 26% (cf. Zh. Obshch. Khim. 1957, 27, 726 English translation in J. Gen. Chem. USSR, p. 799). On the one hand, the reagent is very expensive when used industrially and, on the other hand, the use of tetrachloromethane is undesirable for industrial safety reasons and even prohibited in some countries. Bromination with elemental bromine has hitherto not been successful (cf. Current Sci. (India), 1952, 21, 314 cited in C.A. 48:2046 and Zh. Obshch. Khim.).
The synthesis of 2-bromo-4-ethylthiazole and 2-bromo-4,5-dimethylthiazole by cyclization of α-thiocyanatoalkanones with hydro-bromic acid is known from J. Sci. Ind. Res. Sect. B 1962, 21, 291. Nothing has been published hitherto about an analogous synthesis of 2-bromo-4-methylthiazole, despite the existing need.